S. K.

Jindal
Department of Pulmonary Medicine
Postgraduate Institute of Medical Education and Research
Chandigarh, India
 Spectrum of I.L.D

Connective Tissue
Diseases and Pulm-
renal syndromes
Inherited Inhalational
causes causes

I.L.D.

Granulomatous Specific
• Unknown entities
Idiopathic pulmonary
• Known fibrosis
 JOB DRUGS

IPF

PRIMARY CTD

Schwarz et al In: Murray 2000

1. Symptomatic relief

2. Slow down disease progression

3. Prevent/ Treat complications

4. Prolong survival

5. Improve Quality of Life

6. Prevent drug-induced problems

7. End of Life Care

I. Secondary ILDs

Treatment of ILD of a known primary cause essentially comprises the

treatment of the primary disorder.
 Symptomatic
 Anti-inflammatory
 Supportive

II. Primary ILD (Idiopathic Interstitial Pneumonias) and Pulmonary Fibrosis

 Primary vs. Secondary
 Age of the patient
 Acute vs Chronic Onset
 Active/Progressive
 Severity of symptoms
 Functional and radiological abnormalities
 Treatment of side effects
 Responsive vs Non-responsive (to tmt)
 Early vs End-stage
 Other considerations
1. Symptomatology
2. Chest radiography
3. Pulm. Function Tests
4. BAL ? TBLB/Surgical Bx
5. Scanning – Ga-67,
TC99m DTPA
1. Underlying cause – Identification and management

2. Oxygen therapy

3. Management of pulmonary hypertension and cardiac failure

Pulm. Vasodilators

Diuretics

4. Antibiotics for infections

5. Miscellaneous – Prevention of disease and drug-complications

6. Rehabilitation
 AIP
<1%
IPF/UIP
COP 55% LIP
<1%
3%
?
?
NSIP
25% DIP/ NCIP
RB-ILD
? 15% ?

Garantziotis, J Clin
Invest 2004; 114: 319
 Of all IIPs, Idiopathic Pulmonary Fibrosis (IPF) i.e. U.I.P. is the most
common form.

 It is associated with an extremely poor prognosis for survival in most

patients.

 Life expectancy after diagnosis varies, but is on average less than 5 years.
Old Treatment Algorithm

Jindal et al, Curr Opin Pulm Med

1. Corticosteroids
2. Immunosuppressive drugs
 Azathioprine
 Cyclophosphamide
 Cyclosporine
3. Antifibrotic drugs
 Colchicine
 D-penicillamine
 Pentoxyfylline
4. Anti-oxidants
 N. Acetyl-cysteine
5. Interferon
 The mainstay of therapy has been the use of corticosteroids with or
without immunosuppressive drugs.

Chest 123 (3): 759 (2002).

 Corticosteroids: Prednisolone (1-2 mg/kg)

Induction (3-6 mths)

Maintenance (2-5yrs)

With or without Cytotoxic drugs

 Anti-inflammatory therapies continue to be used despite there being little evidence of
inflammation in the pathogenesis of IPF
 Therapies with anti-inflammatory drugs are associated with toxicity and do not provide
objective benefit

 Although corticosteroid with or without immunosuppressive drugs were the mainstay of

therapy for IPF for decades, their efficacy is unproven and toxicities are substantial .
Am. J. Respir. Crit. Care Med. 171 (9): 939-940 (2005).

Ann. Intern. Med.134:136-151 (2001).

 In a majority of IPF, corticosteroid therapy is only partially effective, and most patients
deteriorate despite therapy.
 There is no controlled trial using corticosteroids alone for the treatment of IPF

Cochrane Database Syst. Rev. 3:CD002880 (2003).

 Any conclusive evidence supporting the use of corticosteroid therapy for the
treatment of IPF is lacking
Eur Respir. J.626:693-702 (2005).

 Given the poor prognosis and the lack of available alternatives or other efficacious
treatments, a therapeutic trial with anti-inflammatory medications is still justified
Thorax 54:S1-S30 (1999).

 IPF respond better to therapy if they exhibit more inflammation and less fibrosis
Better Poor
 Younger age  Old age
 Shorter duration  Acute Exaggeration
 Less severe disease  Complicating illnesses

 Secondary disease
 End stage

Response
Assessment of
3. Spirometry – TLC and VC
1. Symptomatic

2. Chest radiography
 For Against
1. Age Younger (< 50) Older
2. Stage Lessadvanced Severely impaired
(FVC 60-70% pred.) lung function
3. HRCT Nil
or minimal honey Extensive honey
combing combing
4. BAL Lymphos. > 20% Neutropaenic
5. Others Female gender Traction bronchiectasis
Unclear diagnosis of Recurrent LRTIs/
IIP airway colonization
(6 mths trial) Medical comorbidities
 The major anti-fibrotic and anti-cytokine agents that have been used in the
treatment of IPF include:
◦ colchicine
◦ penicillamine
◦ pirfenidone
◦ TGF β antagonist
◦ anti-tumor necrosis factor α (TNF α)
◦ interferon-γ (IFN- γ) and
◦ connective tissue growth factor antagonist
Expert Opin.Emerg. Drugs 10:707-727 (2005).
 Inhibits collagen formation from fibroblasts and may increase collagen
degradation .
 Suppresses the release of alveolar macrophage–derived growth factor and
fibronectin by alveolar macrophages.
 Clinical studies have not shown it to be more effective than
glucocorticoids

Chest. 1993;103:101-4.
 Inhibits collagen synthesis by interfering with collagen cross-linking.
 Suppresses T-cell function .
 Reduced fibrosis induced by radiation and bleomycin.
 Limited studies have not shown efficacy in idiopathic pulmonary fibrosis.

Semin Respir Crit Care Med. 1994;15:77-96.

 Pirfenidone is an anti-fibrotic agent that inhibits TGF- β induced collagen
synthesis in vitro.
 Decreases lung fibroblast proliferation, and downregulates pro-fibrotic
cytokines
 Can diminish BIPF by downregulating platelet-derived growth factor
(PDGF) expression
Am. J. Respir. Crit. Care Med.153:A403 (1996).

 In clinical trials, pirfenidone was able to stabilize both respiratory function

and symptomology.
 N-acetyl Cystine (NAC)

 Nitric Oxide Synthase Inhibitors (Aminoguanidine)

 Cysteine Pro-drugs
 NAC, a derivative of the cysteine amino acid, augments anti-oxidant
glutathione (GSH)synthesis.
N. Engl. J. Med. 353:2285-2287 (2005).

 GSH plays an important role for defense against intra and extracellular
oxidative stress.
 It scavenges free radicals and thus contributes to their reduction.
 Used for its contributory role in IPF.
Receptor Antagonists

-Decorin

-Imatinib Mesylate (PDGF Receptor antagonist)

-Endothelin Receptor 1 Antagonist

Anti-Apoptosis

Myofibroblast induced epithelial cell apoptosis may promote epithelial injury,

aberrant repair responses, and progressive fibrosis

Anti-Angiogenesis

An imbalance of angiogenic and angiostatic chemokines favoring net angiogenesis

is demonstrated with IPF
 Chinese and Japanese granules/ decoctions
 Evidence from bleomycin induced fibrosis

in rodents / Limited clinical trials

Symptom-Relief Preserved DLCO

Qi-dan granules Qi-hong

Ru-yi-ding-chuan Mai-men-dong

Fei-kang granules Kang-xian

Cordyceps sinensis

Kang-xian
Yang et al, Respirology 2009
SDF –1 =
Stromal Cell–
derived
Factor-1
1. Lung Transplantation

2. Palliative End of Life Care

 Domicilliary Oxygen
 Symptomatic relief
 Discontinuation of steroids and immunosuppressive drugs
 Other supports
 Lung transplant is the only therapy of proven benefit in IPF, the 5-year survival
data approach 50 percent.
 Transplantation is reserved for advanced stages of IPF.
 Many patients show improvement with single lung transplantation
FASEB J. 15:2215-2224 (2001).

 Prolongs life and may improve the quality of life.

 Complications: Rejection, infections, others.
 Unavailable in India because of the shortage of donated organs, inadequate
infrastructure and very high costs.
 For patients with hypoxemia (PaO2 < 55 mmHg or SpO2 < 88 percent) at
rest or during exercise.

 Supplemental oxygen relieves exercise-induced hypoxemia and improves

exercise performance in patients with COPD (? ILD).

 Some studies show no difference in QOL between patients receiving

supplemental oxygen compared to those who were not receiving.
 Overall quality of life is impaired in IPF, with specific defects in areas of
physical health and perceived social independence.

 Therefore, patients with IPF should be encouraged to enroll in pulmonary

rehabilitation programs.

 Recent evidence suggests the possibility of benefit from a tailored exercise

program.

 Rehabilitation programs for IPF should be designed to include education

and psychosocial supports with the goal of improving coping skills for a
better quality of life.
 Conventional treatment of IPF with corticosteroids and immunosuppressive agents
has unproven benefit and significant side effects.
 With a better understanding of the pathogenesis there is identification of new
therapeutic approaches.
 Profibrotic growth factors and cytokines act as important intermediaries in driving
disease progression, consequently, modulating their activity is an attractive
approach.
 Several agents with antifibrotic, immunomodulatory, or antioxidant properties are
being evaluated in randomized, controlled trials of patients who have IPF.
 Discontinuation of specific therapy and resorting to palliative care is recommended
for end-stage disease.
 Endogenous tissue stem cells are undifferentiated cells that reside in tissues and
participate in regeneration after injury.
 Adult lung is a vital and complex organ, normally turns over slowly.
 Respiratory system regions are derived from diverse stem or progenitor cells,
differing strategies for maintenance and repair.
 There is potential lung tissue derivation from extrapulmonary BM-derived stem
cells.
 Endothelial, epithelial and mesenchymal elements, contribute to repair and
regeneration in response to injury.
 These cells proliferate from endogenous reparative cells of normal lung resident cells
or may be derived from BM-derived progenitors.
 Soluble cytokine receptors or cytokine-binding proteins that could
compete with cellular receptors for any available secreted cytokine should
effectively inhibit the cytokine’s biological activities.

-Decorin

-Imatinib Mesylate (PDGF Receptor antagonist)

-Endothelin Receptor 1 Antagonist

 Current evidence suggests that increased and continuous epithelial cell apoptosis,
and decreased fibroblast/myofibroblast apoptosis occurred in the process of PF
 Myofibroblasts from patients with fibrotic lung disease secrete soluble factors
(angiotensin peptides) that induce apoptosis of human AEC.
 Myofibroblast induced epithelial cell apoptosis via an oxidant-mediated
mechanism may promote
◦ epithelial injury,
◦ aberrant repair responses, and
◦ progressive fibrosis
FASEB J.19:854-856 (2005).
 Heterogeneity in vascularization in IPF may, on the one hand support
fibroproliferation, and on the other hand, inhibit normal repair mechanisms.
 If neovascularization plays a key role in abnormal matrix remodeling, therapy
directed at either inhibition of angiogenic or augmentation of angiostatic CXC
chemokines could be helpful in IPF.

Am. J. Respir. Crit. Care Med. 170:207 (2004).

 An imbalance in the levels of angiogenic chemokines as compared with angiostatic
chemokines favoring net angiogenesis has been demonstrated with IPF .

J. Immunol. 159:1437Y1443 (1997).

 HMG-CoA reductase inhibitors (statins) induce apoptosis in normal and
fibrotic lung fibroblasts.
 Anti-fibrotic effect of statins is related to their ability to inhibit the
expression of CTGF.
Am. J. Respir. Crit. Care Med.169:A706
(2004).
 Anti-TGF- β antibodies and TGF- β soluble receptors could partially inhibit
fibrosis in bleomycin model .
 Although efficient in animal models, humans could develop immune
reactions against the antibodies.
 GC1008, an antibody that neutralized TGF β, is being investigated for
safety in treating IPF

Pulm. Pharmacol. Ther.19:Mar 3 E Pub (2006).

 IFN- γ -1b regulates both macrophage and fibroblast function.

 It downregulates molecules associated with fibrosis, inflammation, and

angiogenesis.

N. Engl. J. Med. 341(17): 1302-1304 (1999).

 In addition, IFN- γ therapy reduced TGF β expression in lung biopsies

from IPF patients.
 Since epithelial-mesenchymal crosstalk is thought to be important for the
formation of fibroblastic foci, FIZZ-1 may play a significant role in this
process, downstream of IL-13.
 These data suggest that therapies targeting either IL-13 or the IL-13R α 2
receptor may be of interest.
 Study in mice has shown that a recombinant fusion protein composed of IL-
13 and a derivative of pseudomonas exotoxin has efficacy in the bleomycin
model of lung fibrosis.

J Immunol 2003; 171:2684–2693.

Markers: Concept: inflammation
CRP versus fibrosis
sIL-2R
BAL_lym Mainly mononuclear
cell infiltration/proliferation

Sec. fibrosis Primary active

Inflammatory process

Postinflammatory fibrosis
Inflammation
independent?

Primary fibroproliferative process

Markers:
KL-6
BAL_neu
BAL_eos
 Anti-fibrotic drugs that interfere with or modulate further progression of
lung fibrosis may have potential to improve respiratory function
Mayo Clin. Proc. 72:285
(1997)

Anti-cytokine therapeutic strategies are directed at abrogating the activities

of the targeted cytokines that have diverse regulatory activities in several
processes that comprise fibrosis.
 This has been attempted by targeting one or more key steps in cytokine
synthesis and binding to cognate receptors.
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