IS IDIOPATHIC PULMONARY FIBROSIS (IPF) A DUST MITE ALLERGEN-INDUCED DISEASE?

INTRODUCTION

In spite of a substantial progress in medical sciences during the 20th century the pathogenesis of numerous diseases remains unknown and their therapy non-existent. Some of these diseases are terminal and their diagnosis is equivalent to the death sentence. Idiopathic pulmonary fibrosis (IPF) is one of the diseases with unknown etiology, poor prognosis, and prevalence rates of 4.6-16.3 cases per 100,000 individuals. In this manuscript we propose the hypothesis that continuing exposure toward house dust mite allergen(s) could cause a lung fibrosis resembling the IPF. A timely identification of factors capable of inducing IPF could lead to the cure of the disease or control of its progression.

IDIOPATHIC PULMONARY FIBROSIS (IPF)

Pulmonary fibrosis is a pathological process, usually affecting both lungs, and characterized by excessive deposition of fibrous connective tissue and collagen in pulmonary interstitial spaces (1). It is a common feature of various interstitial pneumonias.   Correct identification of the cause of fibrosis determines the prognosis.  The causes have been identified in asbestosis, silicosis, psittacosis or farmer’s lung. The prognosis of these fibrotic diseases is usually favorable, providing patients are no longer exposed to the environmental factors that may have contributed to the disease. The prognosis is poor and the disease is considered terminal if the cause remains unknown as in the case of IPF.  The life expectancy of patients diagnosed with IPF has been estimated as 2 to 5 years, although some of the patients are surviving for more than 10 years after diagnosis (2). The existence of slow and rapidly progressing, as well as familiar and sporadic forms of the disease, suggests that IPF may not be a single disease. No drugs fo0r the treatment of IPF have been approved by Food and Drug Administration (FDA) in the United States of America, although corticosteroids and immunosuppressants are used off-label, mostly with little or no beneficial effect. Pirfenidone has been approved in Japan and European Community for the treatment of IPF and various potential antifibrotic drugs are in preclinical development or clinical trials (3). It is conceivable that the progressive nature of IPF is due to continuous exposure of patients to toxins or allergens that may have caused the disease. Misdiagnosis of IPF is not uncommon. Patients with hypersensitivity pneumonitis, scleroderma, drug toxicity or other pulmonary diseases have been often referred to pulmonary clinics for the treatment of IPF (K.C. Meyer, 2012, Personal Communication). Currently IPF is viewed as a result of interplay of largely unknown genetic and environmental factors. The genetic factors were identified only in a small minority of patients (estimated as 2 to 20% of all IPF patients). For instance genetic defects in surfactant protein A2 have been associated with IPF (4). In some patients with familial IPF mutations in genes encoding RNA components of telomerase have been found (5).

HOUSE DUST MITES AND THEIR ANTIGENS

House dust mites (HDM) are arachnids, related to ticks and spiders. They are 0.5 mm in length and 0.25 mm in width; they can be barely seen with naked eyes, but can be identified using 100 x or higher magnification.  There are at least 30 different species of HDM:  the most abundant species is Dermatophagoides (D.) pteronyssinus.   HDM are present in most homes probably for centuries, although their existence has not been recognized until 1964. It has been estimated that up to 500 HDM can be found in one gram of house dust. Their major source of food is decomposed human or animal skin cells, so that they thrive near humans in mattresses, carpets, pillows and soft furniture. Since the discovery of HDM many articles on all aspects of their taxonomy, physiology and pathology have been published. The most complete source of information on HDM is the book by M.J. Colloff (6).  HDM have been implicated in the pathogenesis of several, mostly allergic diseases, including asthma, rhinitis, keratoconjuctivitis and atopic eczema. The role of HDM in asthma was a subject of International Workshop in 1987 (7). Twenty-one groups of allergens (2-10 in each group) are known to be produced by HDM and many of them can be found in their fecal pellets. Most common allergens, Der p 1 and Der f 1, belong to the Group 1 and are produced by D. pteronyssinus and D. farina, respectively. Der p 1 was purified and characterized in 1980. It is a cysteine proteinase that in addition to its allergenic properties, has been found to disrupt epithelial tight junctions in human pulmonary epithelial cells in vitro and, therefore, promote crossing of epithelial barrier by allergens (8).

The levels of specific IgG for Der p 1 have been found to be higher in serum of individuals known to be exposed to HDM than in non-exposed subjects (9).

HYPOTHESIS

HDM allergens cause in sensitive individuals immediate-type hypersensitivity reaction with production of IgE and activation of mast cells. We are proposing that in some individuals long-term exposure to HDM allergens can lead to chronic hypersensitivity pneumonitis that is often misdiagnosed as IPF. We visualize that long term exposure to HDM allergens may cause chronic inflammation and fibrosis while immediate-type hypersensitivity reaction could be suppressed. Our hypothesis is supported by the fact that dust mites particles smaller that 5µm could reach alveoli (10). Local inflammation favors the formation of pro-fibrogenic growth factors and cytokines (TGFβ, IL-1β, IL-4, IL-5, IL-13, IL-25). Our hypothesis is supported by findings that basophiles, exposed to Der p 1, are known to produce large amounts of cytokines, such as IL-4, IL-5 and IL-13 (11). Furthermore, Der p 1 disrupts tight junctions in lung epithelial cells in vitro (8), as well as barrier function of such human surfactant molecules as SP-A and SP-D (12), effects that can facilitate fibrogenesis and proteolysis of lung epithelial cells. Der p 1 is also likely to activate fibroblasts and promote formation of contractile myofibroblasts directly through its specific protease activating receptors (13), or indirectly through pro-fibrogenic cytokines.

CONCLUSIONS

The progressive nature of IPF, as compared to pulmonary fibrosis of known etiology, is likely due to chronic exposure of patients to HDM allergens that caused the disease originally. The patients develop chronic allergic response leading eventually to massive irreversible fibrosis and death.

The acceptance of our hypothesis should lead to a drastic change in the approach to the treatment of patients with pulmonary diseases of unknown etiology. The patients with idiopathic non-productive cough and/or suspicion of interstitial pneumonia should be advised by their primary healthcare providers to consult an allergist to determine  (using skin prick test or  blood levels of IgG specific for Der p 1) whether they are allergic to HDM extract. In case of a positive finding the patients should be advised to minimize their exposure to the HDM allergens by modifying their environment. This should include encasing mattresses, box springs and pillows into allergen-impermeable covers, removal of carpeting, upholstered furniture, drapes and stuffed toys from their houses, use of only washable bed sheets and covers, lowering humidity and use of air filters. If these changes will not lead to a cure or a substantial improvement in patients’ condition, allergen immunotherapy can be considered (14).

Our hypothesis also points out additional therapeutic targets for the development of novel drugs for patients with pulmonary diseases associated with an allergy to HDM extracts. Antibodies to Der p 1 and/or other HDM allergens as well as Der p 1 – antagonists may be useful in the treatment of IPF.

SUMMARY

The prognosis of pulmonary fibrosis is highly dependent on the identification of its cause by health care providers as well as on patients’ environment and lifestyle. If the cause of the disease is not identified, patients are diagnosed as having IPF, a terminal disease with short life expectancy. The pathology of IPF cannot always be clearly differentiated from that of some of the other lung diseases, including chronic hypersensitivity pneumonitis. Clinical course of IPF can also differ substantially in various patients. We are proposing that some patients, currently diagnosed with IPF, actually suffer from chronic hypersensitivity to dust mite allergens and that in hypersensitive individuals dust mite allergens can induce the release of pro-fibrinogenic cytokines, epithelial damage and eventually fibrosis. This hypothesis leads to new targets and approaches to the therapy of fibrosis, including avoidance of excessive exposure to dust mite allergens, therapeutic use of dust mite allergens antibodies and chemical blockade of dust mite allergens-induced cytokine release.

REFERENCES

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2.       King TE, Jr., Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet 2011;378(9807):1949-61.

3.       Scriabine A, Rabin DU. New developments in the therapy of pulmonary fibrosis. Adv Pharmacol. 2009;57:419-64. Epub 2009 Nov 27.

4.       Wang Y, Kuan PJ, Xing C, Cronkhite JT, Torres F, Rosenblatt RL, et al. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet. 2009;84(1):52-9. Epub 2008 Dec 18.

5.       Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007;356(13):1317-26.

6.       Colloff M.J. Dust Mites. Springer, Netherlands, 2009, ISBN 978-90-481-2223-3

7.     Platts-Mills TAE, Weck de AI, Aalberse AC et al. Dust mite allergens and asthma: a worldwide problem. International Workshop Report. Bull World Health Org 1988, 66(6): 769-80.

8.       Wan H, Winton HL, Soeller C, Tovey ER, Gruenert DC, Thompson PJ, et al. Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J Clin Invest. 1999;104(1):123-33.

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10.     Phillips C, Coward WR, Pritchard DI, Hewitt CR. Basophils express a type 2 cytokine profile on exposure to proteases from helminths and house dust mites. J Leukoc Biol. 2003;73(1):165-71.

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12.     Asokananthan N, Graham PT, Stewart DJ, Bakker AJ, Eidne KA, Thompson PJ, et al. House dust mite allergens induce proinflammatory cytokines from respiratory epithelial cells: the cysteine protease allergen, Der p 1, activates protease-activated receptor (PAR)-2 and inactivates PAR-1. J Immunol. 2002;169(8):4572-8.

13.     Incorvaia C, Fuiano N, Frati F. Allergen immunotherapy: how to balance the different views from pulmonologists and allergists? Immunotherapy.;4(8):853-7. doi: 10.2217/imt.12.79.

IPF- is your diagnosis correct?

I was wrongly diagnosed with idiopathic pulmonary fibrosis (IPF) 9 years ago. According to the medical literature the average survival is only 2 to 3 years after diagnosis. After 5 years I started wondering, why am I still alive? It turns out, it was a wrong diagnosis. I have Deep Vein Thrombosis (DVT) in my left leg for at least 10 years after my fall and leg injury. My left ankle was swelling every night, but there was no pain or any other symptoms. Emboli were traveling to my lungs leading to lung damage that was wrongly diagnosed as IPF. Now I developed pulmonary embolism (PE), a thrombus in the main pulmonary arttery that can be seen on the scan. For the last 10 days I am injecting myself subcutaneously with low dose heparin and taking orally 5 mg warfarin. I am expected to stay on warfarin for at least 6 months. I am also taking prednisone 30 mg once a day orally, and will remain on prednisone probably for another month (total 3 months). In 6 to 12 months I may even recover completely.
The wrong diagnosis of IPF is apparently not uncommon. K.C. Meyer, M.D. (Director of Interstitial Lung Disease Clinic at the Univ. of Wisconsin UW) in his Update on Clinical Trials for IPF (on Internet) lists 12 alternative diagnoses made at UW in patients claimed to suffer from IPF. They are: lymphangitic carcinoma, hypersensitivity pneumonitis, polyomyositis, scleroderma, Langerhans cell histiocytosis, NSIP, DIP, RBILD, chronic aspiration, sarcoidois, congestive heart failure, drug toxicity. DVT and PE should be now added to this list!
The DVT and PE diagnosis in my case was made by Erica Herzog, M.D., PhD, Yale Pulmonary Clinic. She questioned the cause of my left leg swelling and ordered ultrasound that revealed DVT.
Keywords: Idiopathic pulmonary fibrosis; deep vein thrombosis, pulmonary embolism; warfarin, prednisone,

VARGATEF

Vargatef (BIBF-1120)is a multikinase inhibitor under development by Boehringer-Ingelheim primarily as an antiangiogenic and antineoplastic (ovarian and non-small cell lung cancer) agent. It inhibits kinase receptors that mediate the effects of vascular endothelial growth factor (VEGF), platelet derived (PDGFalpha), fibroblasts growth factor (FGF) and Src family of kinases (Lck, Lyn, and FLT-3). Cell proliferation is inhibited by vargatef at 10-80 nmol/L. Currently 18 clinical trials with Vargatef in cancer and 3 in idiopathic pulmonary fibrosis (IPF) are listed on Clinicaltrials.gov. One Phase I safety study and one Phase II study with Vagatef in patients with IPF have been completed, but the results of the phase II trial have not been posted by the sponsor. Another trial is being planned in Japan.

Ambroxol

Ambroxol is an old drug, It has been developed and marketed in Germany by Boehringer-Ingelheim in 1970s as a mucolytic agent. It is currenly available as a drug in 18 countries, including Germany, India and Russia, but not USA or Canada. It can be purchased in large amounts from Chinese chemical manufacturing companies and in small amounts for experimental use from Western chemical supply houses (e.g. Tocries Biosciences). There is no known safety issue with ambroxol, although one case of rhabdomyolysis has been reported in a patient who was treated with ambroxol as well as other drugs. Apparently, Boehringer-Ingelheim did not apply for registration of ambroxol in USA when the drug was still under patent. After patent expiration its marketing for the same indication did not make any commercial sense.

Over the last 30 years ambroxol was studied extensively in various laboratories. Currently (2010) Medline lists 343 references to pharmacological or clinical studies with ambroxol. Malerba and Ragnoli reviewed 40 years of publications on pharmacological and clinical findings with ambroxol (1). In a more recent review article Gupta emphazised the need for well conducted clinical studies with ambroxol in severe obstructive airway disorders (2). Ambroxol was found to increase production of lung surfactant protein, to have antiinflammatory, antioxidant, local anesthetic, analgesic activities as well as to inhibit neuronal sodium channels and reduce murine influenza virus proliferation. Ambroxol was shown to reduce production of proinflammatory cytokines, including platelet derived growth factor (PDGF), TNFalpha, IL-1, IL-10 and IL-12(3-7). In some, paticularly severly ill, patients ambroxol reduced acute exacerbations of chronic pulmonary obstructive disease (e.g. COPD)(8). The pharmacological profile of ambroxol, in particularly, its ability to reduce release of cytokines, suggests its possible usefulness not only in obstructive diseases, but also in pulmonary fibrosis. Its clinical evaluation as a sole or adjunctive therapy of idiopathic pulmonary fibrosis (IPF) is indicated.

1. Malerba M., Ragnoli B. Ambroxol in the 21st century: pharmacological and clinical update Expert Opinion on the Drug Metabolism and Toxicology. 2008:4:1119-29.
2. Gupta R.R. Ambroxol - Resurgence of an old molecule as an antiinflammatory agent
in chronic obstructive airway disease. Lung India: 2010:22:, 46-9.
3. Betz, R. Glukokortikosteroide und Ambroxol hemmen die Sekretion entzuendungsfoerdernder Zytokine in tracheobronchialen Epithelzellen; Moegliche Rolle des Transkriptionsfaktors NF-kappaB. Pneumologie, 1997:51: 491-2.
4. Gibbs, B.F., Schmutzler W., Vollrath, I.B., Brosthardt P., Braam U., Wolff, H.H.,Zwadlo-Klarwasser, G. Ambroxol inhibits the release of histamine, leukotrienes and cytokines from human leukocytes and mast cells. Inflammation Research, 1999:48:86-93.
5. Alhara M., Dobashi K, Aklyama M, Naruse I, Nakazawa T, Mori M. Effect of N-acetylcysteine and ambroxol on the production of IL-12 and IL-10 in human alveolar macrophages. Respiration. 2000: 67:662-71.
6.Utsugi M., Dobashi K., Kogo Y., Masubuchi K., Shimizu, Y., Endou K., Nakazawa T., and Mori M. Ambroxolinhibits platelet derived growth factor production in human monocytic cells.Eur J Pharmacol 2002: 436:47-51.
7. Gaida W., Klinder K., Arndt K., Weiser T., Ambroxol, a Nav 1,8-preferring Na(+)
channel blocker, effectively suppresses pain symptoms in animal models of chronic, neuropathic and inflammatory pain. Neuropharmacol 2005:49:1220-7

TRANILAST IN PULMONARY FIBROSIS

Tranilast (RIZABEN) is an old antiallergic drug, it is sold in Japan by KISSEY Pharmaceutical company for the treatment of allergies and also hypertrophic scar formation. Nuon Pharmaceuticals (San Mateo,CA) is developing it for new indications, including gout, rheumatoid arthritis and MS. Considerable amount of information on its pharmacology is available. Tranilast has been found to inhibit collagen synthesis in fibroblasts, decrease production of IL-6 and IL-8, inhibit VEGF-induced proliferation and migration of vascular endothelial cells, and to bind to aryl hydrocarbon receptors. These and other findings suggest that tranilast could be useful in the treatment of pulmonary fibrosis. Unfortunately, no clinical studies
in this indication are available or even planned.

Missing drugs

Idiopathic Pulmonary Fibrosis (IPF) is one of one of many diseases for which there is no Food and Drug Administration (FDA) approved drugs in USA. This does not mean, however, that there are no drugs of possible benefit for this disease. Based on the recommendation of Thoracic Society some pulmonary physicians prescribe glucocorticoids (e.g. prednisone) with or without immunosuppressants (e.g. azathioprine) . Only occasional benefit has been reported with this approach. Without FDA approval or recommendation of a professional society physicians are understandably reluctant to prescribe drugs that can conceivably be useful in the treatment of IPF, although they have right to prescribe drugs off-label. The reasons for this reluctancy include potential lawsuits and cost of malpractice insurance. There is also no readily available information source on the off-label use of drugs approved for other indications. Neither FDA, nor textbooks or databases provide such information and pharmaceutical companies are strictly prohibited to inform physicians about potential off-label indications for their drugs. One of the drugs used off-label in IPF is N-methyl-acetylcysteine (known also as NAC), a glutathione precursor and powerful antioxidant and hepatoprotective. In USA NAC is approved and commercially available (ACETADOTE) as an antidote for acetaminophen intoxication, but not other indications. Its usefulness in the therapy of IPF in combination with glucosteroids was suggested by a clinical trial (1), that led to still more ongoing trials. Since NAC's toxicity is very low and there is an urgent need for IPF therapeutics, NAC should be made available to all IPF patients. Fortunately, it is available also as a dietary supplement from Puritan's Pride, although this company cannot provide any information on its use in IPF. Even if additional clinical trial confirm effectiveness of NAC in IPF, it will probably never become a standard IPF therapeutic, since no pharmaceutical company will be capable of covering the cost of NAC development for this new indication without use patent coverage. NAC's availability for a very low cost as a dietary supplement will also further complicate its development as an IPF drug.

IPF SYMPTOMATOLOGY

Since Idiopathic Pulmonary Fibrosis (IPF) may not be a single disease, it is not surprising that disease symptoms may vary among patients. Also in the same patient the symptoms may differ with the stage of the disease. A chronic postnasal drip was my first symptom. I attributed subsequent attacks of non-productive cough to throat irritation caused by nasal discharge due to sinus infection. I consulted otorhinolaryngologist who found no evidence of any sinus disease. The persistent cough attacks in the mornings led my family physician to refer me to a radiologist for a chest X-ray and subsequently to a cardiologist because of slight right heart enlargement. Cardiologist found no evidence of heart failure and referred me to a pulmonologist who made a tentative diagnosis of IPF on the basis of X-ray, catscan and pulmonary function test.
At ca 3 years after the initial diagnosis I first experienced oxygen desaturation on exercise. Now, at 8 years after diagnosis, this is my major symptom. My arterial blood oxygen levels decrease from 95% at rest to as low as 83% after a few steps around the house. Desaturation is always associated with tachycardia, my heart increases from 70 or 80 beats/min to 110 or even 120 beats/min. Oxygen inhalation reduces desaturation effect but not necessarily cardiac acceleration. Postnasal drip is now replaced by frontal nasal discharge that is enhanced by oxygen inhalation. Another symptom at the late stage of the disease is a disturbance in temperature regulation. A burning feet sensation appears to be independent of either oxygen saturation levels or of actual skin temperature. If oxygen saturation is lowered below 90% an attack of dry cough is likely to follow, but occasionally I had cough attacks even at normal blood oxygen levels. Another symptom of the disease is weight loss; I started to loose weight at ca 6 years after diagnosis and lost ca 25 pounds within the last two years.
Hypersensitivity diseases are often associated with skin eruptions. I experienced eruptions in anal region that responded to local antihistaminics or steroids. These eruptions may indicate hypersensitivity to a dietary component, cytokine or a bacterial toxin. They may conceivably help in the elucidation of the etiology of my disease.

Pirfenidone - comment to FDA

On 5.26.10 I forwarded the following comment to Food and Drug Administration:
The decision of the Food and Drug Administration (FDA) not to approve pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF) was highly disappointing to all patinets suffering from this disease, their caregivers, as well as physicians who are treating IPF patients. The fact that that the Agency did not follow the advice of their Advisory Committee, which voted 9:3 for the approval of pirfenidone, is extremely disturbing. The Agency also did not listen to pleas of patients who have been waiting impatiently for any drug that could possibly offer some hope in alleviating their suffering or prolonging their life expectancy. The Agency found it impossible to deviate from the established guidelines, even though the safety of pirfenidone was not quetioned.
The request for another Phase III trial to confirm the efficacy of pirfenidone may sound reasonable, but in reality it makes the eventual marketing of pirfenidone unlikely, even if another trial confirms its efficacy. Al leaast 4 years and a few hundred millions of dollars will be needed for another trial and its evaluation. If the trial starts in 2011, FDA approval cannot be expected before 2015. The proposed use of pirfenidone in IPF is covered, however by a 1997 patent that will expire in 2014. No single pharmaceutical company can afford to pay for the development and marketing of a drug without patent protection and/or a few years of exclusivity.
No drug can be expected to produce absolutely conclusive results in patients with IPF. IPF is most probably not a single disease but a collection of fibrotic lung diseases with unknown causes, so that in respect to etiology the patient population will be heterogenous and pirfenidone cannot, therefore, be expected to help all IPF patients. The fact that pirfenidone helps some of the patients with IPF should provide an adequate basis for its approval, since the risk-benefit ratio favors the drug.
A possible solution for the FDA is to create a new category of drugs with only "conditional approval" which would not cary an approved disease indication, but would claim, like for "dietary supplements", only a possible supporting role in the maintenance of function of certain organs (lungs in the case of pirfenidone). These drugs could be conditionally appproved by FDA on the basis of their safety record and the medical profession could be responsible for their use in specific diseases. This "conditional approval" could be withdrawn after 5 years, if additional documentation is not provided. After completion of all required clinical trials a final approval would be considered. In any case, I hope that the FDA would be willing to reconsider or to modify their decision to request another Phase III trial for pirfenidone.
Sincerely, Alexander Scriabine, M.D., Guilford, CT, May 26. 2010
Pharmacologist and IPF patient

FDA meeting on pirfenidone
FDA Advisory Committee is meeeting on March 9 2010 to consider approval of pirfenidone for the treatment of pulmonary fibrosis. I am submitting the following opinion to FDA to be considered at this meeting:

My Experience with Idiopathic Pulmonary Fibrosis (IPF)

I am a retired MD pharmacologist and for the last 9 years an IPF patient.

As a patient I experienced an unusually slow progression of the disease: a gradual suffocation leading to a loss of my ability to run, climb stairs and now even walk without oxygen. Attacks of a severe unproductive cough have made the life particularly miserable. I am a patient at Yale pulmonary clinic but the best pulmonary physicians cannot cure me. I am not eligible for lung transplantation and my therapy consists only of oxygen, since there are no drugs capable of alleviating my suffering. In the clinic I am having annual pulmonary function tests to document a gradual decline in most parameters. There is also a support group of patients with IPF to share experiences. I am learning that some of the patients are in worse shape than I am. They are in wheelchairs and can no longer dress or take a shower without the help of a caregiver. I can see myself in a similar situation in the near future.

As a scientist I am deeply disturbed by our failure to recognize the medical need and to develop drugs for the treatment of IPF. Very little research is ongoing in this field at either academic institutions or the pharmaceutical industry. I spent a good portion of the last year researching IPF and the approaches to its therapy. My research culminated in an extensive review article published last December (Scriabine A and Rabin D.U.. New developments in the therapy of pulmonary fibrosis. In: Contemporary aspects of biomedical research: drug discovery. Enna S.J. and Williams, M. Eds. Academic Press 2009; 419-464). Targets for antifibrotic drugs have been proposed and models of fibrotic diseases are available, but only pirfenidone offers some hope for IPF patients in the near future. IPF is probably not a single disease, but a group of pulmonary diseases with similar pathology, but different etiology. If so, one drug is not likely to help every patient diagnosed with IPF and clinical trials will not demonstrate uniform efficacy in a heterogeneous population. Under these circumstances safety should be the major consideration for drug approval.

Alexander Scriabine, MD
ascriabine@comcast.net
435 Colonial Road
Guilford, CT 06437

Pulmonary Alveolar Proteinosis (PAP) vs Idiopathic Pulmonary Fibrosis (IPF) - Diagnostic Considerations
PAP is a rare clinical syndrome that is characterized by the accumulation of surfactant in the pulmonary airspaces (Greenhill SR and Kotton DN, 2009). Lung biopsies usually reveal presence of diastase-resistant intra-alveolar exudate with minimal interstitial fibrosis and "honeycombing". In some patients with PAP, however, interstitial fibrosis can be considerable and at least two PAP patients were initially thought to have IPF (Arbiser ZK et al., 2003). PAP is no longer idiopathic, since functional deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF) appears to cause the disease. The presence of autoantibodies against GM-CSF in serum is considered to be diagnostic for PAP (Kitamura T et al., 1999; Bonfield, TL et al., 2002). It is highly important to excude PAP as a possible diagnosis since the prognosis of PAP and IPF are different. The life expectancy of PAP patients is longer, 5-year mortality is 20% vs 80% for IPF patients. Also, patients with PAP favorably respond to pulmonary lavage and can possibly be treated with GM-CSF. It is unfortunate that GM-CSF antibodies test is not yet widely available in clinical laboratories.
Arbiser ZK et al. Ann Diagn Pathol 7:82-86, 2003
Bonfield TL et al. Clin Immunol 105:324-350, 2002.
Greenhill SR and Kotton. Chest 136:571-577, 2009
Kitamura T et al. J Exp Med 190:875-880, 1999.

IPF symptomatology

The first symptom of my disease, idiopathic pulmonary fibrosis (IPF), was cough. It appeared to be caused by a post-nasal drip. I assumed that my sinuses may have been infected and I contacted otolaryngologist who ordered scan of the sinuses and found nothing. The cough was initially non-productive, it lasted for ca 30 minutes every morning and subsided after breakfast. IPF was diagnosed at Yale pulmonary clinic on the basis of X-ray, pulmonary function tests and lung scan. It was explained to me that IPF is a terminal disease and that there are no FDA approved drugs for the treatment of IPF. The only therapy, recommended by the Thoracic society, consists of steroids (e.g. prednisolone) and/or immunosuppressants (e.g. azathioprine). This therapy has not been shown to prolong life expectancy, is ineffective in the majority of patients and is associated with substantial side effects. I chose not to be treated and used candies to reduce the severity of cough. I learned from the literature that antioxidants may have antifibrotic activity and treated myself with vitamin C (slow release), 1 g per day and N-acetyl cysteine ( 2 x 600 mg per day). The only other symptom I experienced early in the disease was what I called, "miniapnea", inability to breathe for a few seconds, followed by complete recovery. Thereafter, dyspnea during and after exertion became the major symptom.
Initially it was uphill walking that caused dyspnea, but gradually walking on the flat surface became difficult as well. Dyspnea was associated with oxygen desaturation, as measured with oximeter. Climbing steps to the 2nd floor at home reduced blood oxygen saturation very rapidly from 95% to 85 and eventually even to 78%. Breathing oxygen at 2 L/min for 5 to 10 minutes normalized oxygen levels. Desaturation below 90% was associated with dyspnea, dizziness, anxiety and occasional chest pain. The symptoms were proportional to the decrease in blood oxygen, they rapidly disappeared after oxygen inhalation. Thermoregulation appeared to be affected as well. Exposure of the skin to cold temperature led to oxygen desaturation and cough.
Another symptom was "burning feet" at night that was independent of actual skin or room temperature. The sensation was the same when the feet were hot or cold. Still another symptom was "running nose", nasal discharge of a very thin fluid, that was more pronounced during and after administration of oxygen.
Domestic tasks became difficult, I routinely desaturated in shower and switched to bath every second day. Initially, I could exercise on treadmill while inhaling oxygen, but later oxygen inhalation even at 3 L/min did not protect from desaturation during exercise. The disease appeared to progress in steps. The steps were initiated by common cold or other stress. Annual lung function tests indicated gradual decrease in vital capacity. I found it more and more difficult to maintain blood oxygen levels above 90%. According to the literature only 20% of patients are expecxted to survive 5 years after diagnosis. I am already in my 8th year. Does this mean that diagnosis may have been incorrect?

October 6, 2009

Antioxidants in the treatment of IPF (idiopathic pulmonary fibrosis)

The disturbance of pulmonary antioxidant/oxidant balance leading to oxidative stress is thought to be one of the major factors contributing to the development of IPF ( Kinnula and Myllärniemi, 2008; Walters et al., 2008). In patients with IPF there is an excessive production of so-called reactive oxygen species (ROS): superoxide anion (O2-), hydrogen peroxide (H2O2), peroxynitrite and hydroxyl radicals (OH-). ROS damage proteins, lipids and other cellular macromolecules, activate profibrotic cytokines, and consequently enhance fibrosis. Production of ROS is increased in animals with bleomycin-induced fibrosis and ROS are required for the development of bleomycin-induced fibrosis in mice (Manoury et al., 2005). In animals fibrosis can be prevented or reduced by antioxidants (Kilinç et al, 1993). Taken together these data support the notion that antioxidant therapy may have a beneficial effect in the treatment of IPF.
Many antioxidants occur naturally in the body and/or are regularly present in the human diet. Glutathione, vitamins E and C, polyphenols and uric acid belong to this group. Numerous antioxidant polyphenols are present in plants, vegetables and fruits. Indeed, curcumin (Biswas et al., 2005) and resveratrol (Sener et al., 2007) ameliorate bleomycin-induced pulmonary fibrosis in rats. Glutathione is a major antioxidant in lungs. In addition to its antioxidant activity, glutathione suppresses the proliferation of human lung fibroblasts (Cantin et al., 1990) and regulates the fibrogenic effects of transforming growth factor beta (TGFβ) (Ono et al., 2009). Since glutathione does nor readily penetrate the cell membrane, and has bronchoconstrictor activity, most experimental studies were performed with its thiol precursor, N-acetyl cysteine (NAC). Other thiols or prodrugs known to be metabolized to thiols, such as erdosteine, have also been shown to prevent bleomycin-induced fibrosis in laboratory animals (Day, 2008). Animal studies strongly suggest that NAC and other antioxidants should be useful in the therapy of patients with IPF.

Biswas, S.K., McClure, D., Jimenez, L.A., Megson, I.L, and Rahman, I. (2005). Curcumin induces glutathione biosynthesis and inhibits NF-kappaB activation and interleukin-8 release in alveolar epithelial cells: mechanism of free radical scavenging activity. Antioxid. Redox. Signal. 7:32-41.

Cantin, A.M., North, S.L., Felis, G.A., Hubbard, R.C., and Crystal, R.G. (1987). Oxidant-mediated epithelial cell injury in idiopathic pulmonary fibrosis. J. Clin. Invest. 79:1665-1673.

Day, B.J. (2008). Antioxidants as potential therapeutics for lung fibrosis. Antioxid. Redox Signal. 10:355-371 .

Kilinç, C. Ozean, O,. Karaoz, E., Sunguroglu, K., Kuluay, T., an Karaca, L. (1993). Viamin E reduces bleomycin-induced fibrosis in mice: biochemical and morphological studies. J. Basic. Clin. Physiol. Pharmacol. 4: 249-269.

Kinnula V.L. and Myllärniemi, M. (2008). Oxidant-antioxidant imbalance as a potential contributor to the progression of human pulmonary fibrosis. Antioxid. Redox. Signal. 10: 727- 738.

Manouri, B., Nenan, S., Leclerc, O., Guenon, I., Boichot, E., Planquois, J-M., Bertrand, C.P., and Lagente, V. (2005). The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis. Respir. Res. 6:11-23.

Ono, A, Utsugi, M., Masubuchi, K., Ishizuka, T., Kawata, T., Shimizu, Y., Hisada, T., Hamuro, J., Mori, M., Dobashi, K. (2009). Glutathione redox regulates TGFβ –induced fibrogenic effects through Smad3 activation. FEBS Lett 583: 357-362.

Sener, G., Topaloglu, N., Sehirtli, A.O., Ercan, F. and Gedik, N. (2007). Resveratrol alleviates bleomycin-induced lung injury in rats. Pulm. Pharmacol. Ther. 20:642-649.

Walters, D.M., Cho, H-Y and Kleeberger, S.R. (2008). Oxidative stress and antioxidants in the pathogenesis of pulmonary fibrosis: a potential role for Nrf2. Antioxid. Redox Signal. 10:321-332.

Animal Models of Pulmonary Fibrosis

Reliable animal disease models greatly facilitate drug development, even when the precise trigger of a disease is unknown. Since this is the case with idiopathic pulmonary fibrosis (IPF), the availability of an animal model is particularly important for successful development of antifibrotic drugs. The standard models of pulmonary fibrosis are bleomycin-treated rodents. Extensive reviews of the bleomycin model and of its use in pulmonary research were recently published (Moeller et al., 2008). A single intratracheal administration of bleomycin produces pulmonary fibrosis in rodents, with a maximal effect at between 20 to 28 days after exposure to the drug. Thereafter fibrosis slowly resolves. The cause and the spontaneous resolution of fibrosis differentiate this model from IPF in humans, although it is similar with respect to the production of cytokines and free radicals. Moeller et al. listed published studies on the prevention or treatment of bleomycin-induced fibrosis in laboratory animals. They point out that to mimic clinical situations the potential antifibrotic drugs should be administered after, and not prior to, the development of bleomycin-induced fibrosis. Antioxidants, angiotensin converting enzyme inhibitors, angiotensin antagonists, immunosuppressants, macrolide antibiotics and many other agents are reported to reduce fibrosis in bleomycin-treated animals. Most of the drugs were never tested for antifibrotic activity in humans whereas others were ineffective in clinical trials. However, the fact that pirfenidone is effective in this model, and has yielded promising clinical results in a Phase III trial, suggests the potential utility of this model in drug discovery.
Other drugs or chemicals known to produce pulmonary fibrosis in humans are also
used in the search for potential antifibrotic drugs. For example, Cantor et al. (1984) produced amiodarone-induced fibrosis in hamsters, while Leeder et al. (1994) demonstrated a reduction of amiodarone-induced pulmonary toxicity by N-acetyl cysteine (NAC). Pulmonary fibrosis can be also produced in rats by paraquat and the angiotensin converting enzyme inhibitors captopril and enalapril reduce paraquat-induced pulmonary fibrosis in rats (Ghazi-Khansari et al., 2007). Parra et al. (2008) induced pulmonary fibrosis in mice by butyl-hydroxytoluene and found it to be histologically identical to fibrosis in humans with IPF. Ask et al. (2008) have induced pulmonary fibrosis in rats by adenoviral gene transfer of transforming growth factor beta (TGFβ) and assessed progression of the disease by non-invasive techniques.
Attempts have also been made to develop in vitro models of pulmonary fibrosis. As an example, cadmium chloride in combination with TGFβ produces fibrosis in rat lung slice cultures (Lin et al., 1998).
The adequate technology for the preclinical evaluation of potential antifibrotic drugs is available, although it is obvious that neither animal models nor in vitro techniques mimic the human condition in all respects.

Ask, K., Labiris, R., Farkas, L., Moeller, A., Froese, A., Farncombe, T., McClelland, G.B., Inman, M., Gauldie, J., and Martin, R.J. (2008). Comparison between conventional and “clinical” assessment of lung fibrosis. J Transl Med 6:16.

Cantor, J.O., Osman, M., Cerreta, J.M., Suarez, R., Mandi, I., and Turino, G.M. (1984). Amiodarone-induced pulmonary fibrosis in hamsters. Exp. Lung. Res. 6:1-10.

Ghazi-Khansari, M., Mohammadi-Karakani, A., Sotoudeh, M., Mokhtary, P., Pour-Esmaeil, E., Maghsoud, S. (2007). Antifibrotic effect of captopril and enalapril on paraquat-induced fibrosis in rats. J. Appl. Toxicol. 27:342-349.

Leeder, R.G., Brien, J.F., and Massey T.E. (1994). Investigation of the role of oxidative stress in amiodarone-induced pulmonary toxicity in the hamster. Can. J. Physiol. Pharmacol. 72:613-621.

Lin, C.J., Yang, P.C., Hsu, M.T., Yew, F.H., Liu, T.Y., Shun, C., Tyan, S.W., and Lee, T.C. (1998). Induction of pulmonary fibrosis in organ-cultured rat lung by cadmium chloride and transforming factor –beta1. Toxicology 127: 157-166.

Moeller, A., Ask, K., Warburton, D., Gauldie, J., and Kolb, M. (2008). The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis? Int. J. Biochem. Cell Biol. 40:362-382.

Parra, E.R., Boufelli, G., Berthanha, F., Samorano, Lde.P., Aguiar, A.C. Jr., Costa, F.M., Capelozzi, V.L., Barbas-Filho, J.V. (2008). Temporal evolution of epithelial, vascular and interstitial lung injury in an experimental model of idiopathic pulmonary fibrosis induced by butyl-hydroxytoluene. Int. J. Exp. Pathol. 89:350-357.

Alex Scriabine, MD
Guilford, CT

WHERE ARE DRUGS FOR TREATMENT OF IPF (IDIOPATHIC PULMONARY FIBROSIS)?_

During the last decade extensive research has been conducted on IPF and therapeutic approaches to treat this condition. New targets for drug development, as well as new leads, were identified. However, there are still no FDA-approved drugs for the treatment of this condition

There have been several barriers to the development of effective therapeutics for IPF. One is the fact that IPF is considered an orphan disease because of its prevalence, lessening the urgency for finding a cure. Moreover, the pharmaceutical industry underestimates the medical need and the potential profitability of antifibrotic drugs. Because the population in developed countries is rapidly aging, IPF is becoming a more common disorder. It is anticipated that companies will begin to look more favorably on drug development in this area as it is becoming apparent that fibrotic diseases as a group may share the same therapeutic targets. In this case, drugs developed for the treatment of pulmonary fibrosis may be useful in the therapy of renal, myocardial, hepatic and other fibrotic diseases as well, broadening the use of such agents.

The complexity of fibrogenesis and the multiplicity of profibrotic and antifibrotic factors, are other reasons for the failure to develop effective drugs. With the advancement of basic research in fibrosis many new targets for drug development have been discovered. However, these discoveries have yet to be translated through to drug discovery and clinical testing. In addition, the consolidation of the pharmaceutical industry has resulted in more focused research programs and less enthusiasm for undertaking higher risk projects that lack “proof of concept”.

There is also a justifiable skepticism about the relevance of the in vitro or animal research methodology that is currently used in drug discovery. The findings of cell culture experiments are not always applicable to the whole organism, and results obtained in mice or rats may not be relevant to humans. Although the bleomycin-induced fibrosis in rodents test tends to identify false positive leads, it might be most relevant in the “therapeutic” rather than the “preventive” protocol. Animal models are often more sensitive than patients in clinical trials, as experimental animals are homogenous in genetic background, sex, age, weight, general health and diet. Compounds which are safe and effective at reasonable doses in a “therapeutic” protocol of bleomycin-induced fibrosis should be considered for optimization and eventual clinical evaluation.

Lack of patentability, toxicity, ignorance of the molecular target or questionable “drugability” of potential antifibrotic drugs are common barriers to their development. In today’s highly competitive environment, few companies are willing to pay for the development of a generic agent like N-acetyl cysteine for the treatment of IPF without proprietary protection. Also, some of the drugs identified as antifibrotics belong to chemical classes known for their toxicity, extensive metabolism, or poor bioavailability and, therefore, are not considered good candidates for development.

It is conceivable that a blockade of only one profibrotic factor cannot stop or reverse fibrogenesis. A drug combination product designed to affect multiple fibrogenic pathways may be required for the effective therapy of IPF.
Another strategy is to search for drugs to enhance resolution of fibrosis. It has been shown that experimental hepatic fibrosis in rodents can be resolved by drugs. The reversibility of pulmonary fibrosis is a controversial subject. It has been suggested that in pulmonary fibrosis the loss of basement membrane, and consequently of normal lung architecture, establishes the point of no return.. Perhaps at earlier stages of the disease pulmonary fibrosis is reversible. Unfortunately, the mechanism of resolution of fibrosis is poorly understood and only a few approaches for the development of fibrolytic targets have been identified.
A better understanding of fibrogenesis and fibrolysis will greatly facilitate discovery and development of new antifibrotic drugs. Based on past experience, many more years are needed to advance the knowledge base of this field to a level adequate for successful design and development of drugs capable to selectively modifying fibrosis in humans. In the interim, available leads should be optimized on the basis of their activity in mice with bleomycin-induced fibrosis or a similar model. If the endpoint of a clinical trial is mortality, the same endpoint should be used in an animal model.
There is also an urgent need for better biomarkers for use in clinical trials. The duration of trials of drugs for treating IPF can be substantially reduced in time and cost if mortality is replaced by an endpoint based on a meaningful biomarker.

The histories of pirfenidone in pulmonary fibrosis reveal several important issues with drug development. The antifibrotic effectiveness of pirfenidone in animals has been known for 14 years and in humans for 10 years. However, resounding proof of its efficacy in human IPF is still not available. This illustrates the imperfect nature of the drug development process and a lack of focus on fibrotic diseases in the pharmaceutical industry.

IPF

September 19, 2009
IPF or Idiopathic Pulmonary Fibrosis is a chronic interstitial pneumonia of unknown cause and poor prognosis. The life expectancy of IPF patients has been estimated as 2 to 3 years after diagnosis. IPF is characterized by clinical, radiologic and histologic criteria. The frequently used therapy of steroids (prednisolone) and immunosuppressants (azothioprine) has not been shown to be effective. No drugs for the therapy of IPF are approved in the USA. Bosentan, pirfenidone and N-acetyl cysteine are currently in clinical trials with preliminary results suggesting they may prolong the life expectancy of patients with IPF. New approaches to the treatment of IPF have been proposed. They include endothelial and cytokine antagonists, and antioxidants. Japanese health authorities approved pirfenidone (Shionogi) for the tretment of IPF earlier this year. Additional clinical studies are neeed for its approval by Food and Drug Administration in the USA. Pirfenidone is and old drug and its possible usefulness in the therapy of IPF has been known for over 15 years. Why does it take so long to make pirfenidone available to IPF patients in this country? My blogs will try to answer this question and explore other possible approaches to the therapy of IPF.
Alex Scriabine, MD pharmacologist and an IPF patient.